As to the compound used in the present invention, a free compound thereof, i.e. the compound of formula (II)
is described in example 2 (63) of JP kokai hei 3-20253 (i.e. EP 347168) and a monosodium salt tetrahydrate thereof of formula (I)
(at times abbreviated as compound (I)) is described in example 3 of JP kokai hei 5-194366 (i.e. EP 539223) and in reference example 1 of JP kokai hei 9-40692 (no EP publication).
Compound (I) has an inhibitory activity against elastase and is a very useful compound which is expected to be used for the treatment of acute pulmonary disorders. Since those patients suffering from acute pulmonary disorders are in a serious condition, it is necessary to administer a drug parenterally, preferably as an injection for a long time (from 24 hours to several days) continuously. Therefore compound (I) is appropriately formulated as an injection or a solid composition to be dissolved before administration, more preferably formulated as a freeze-dried product. And considering the convenience, a high-dosage product in a small vial compared with the amount of active ingredient is preferable.
By the way, in the manufacturing process of a freeze-dried product, generally, a drug needs to be kept in a clear solution. That is because suspension and emulsion do not give a certain concentration and may cause a problem such as blockade of nozzles of the filling equipment as well.
Considering the effective dose of compound (I) and the volume of suitable closed containers (vials, ampoules, etc.), for the manufacture of a high-dosage freeze-dried product of compound (I), the required solubility is estimated to be 80 mg/mL or more in subjecting to freeze-drying.
However, compound (I) is hardly soluble in water or ethanol; the solubility is 0.4 mg/ml in water, and 6.0 mg/ml in ethanol. Therefore, by normal solvents it is difficult to prepare a clear solution for the process of a high-dosage freeze-dried product.
JP kokai hei 9-40692 discloses a method for the preparation of compound (I) by suspending a compound of formula (II) to a mixed solvent of water and ethanol, adding an aqueous solution of sodium hydroxide thereto, heating and then cooling. This operation shows a method for the preparation of a sodium salt tetra-hydrate from a free carboxylic acid of formula (II) but does not disclose a freeze-dried product of sodium tetra-hydrate of formula (I).
JP kokai hei 5-194366 discloses a method for the preparation of freeze-dried product of compound (I) by using sodium carbonate and water, but the method does not accomplish to give a solubility of 80 mg/mL or more, which is the level which the present invention intends to overcome.
Additionally, it proved that the pH of the freeze-dried product manufactured according to the above method was ascended in the time course and may decompose compound (I), so it is not necessarily preferable.